	D₁	D₂
Effect of stimulation on cyclic AMP production	Increased	Decreased
Greatest concentrations	Striatum, limbic system, and cerebral cortex	Striatum, substantia nigra
Effect of dopamine	Weak agonist	Strong agonist
Effects of dopamine agonists	Vary with agonist	Strong
Effect of phenothiazines	Strong antagonist	Strong antagonist
Effect of butyrophenones	Weak antagonists	Strong antagonists
Effect of clozapine	Weak antagonist	Weak antagonist

When antipsychotics block D₂ receptors, the reduced dopamine activity induces parkinsonism, raises prolactin production (inducing galactorrhea), and places patients at risk for tardive dyskinesia. Some atypical antipsychotic agents, particularly risperidone and its active metabolite paliperidone (Invega), raise prolactin serum concentration and induce galactorrhea. Even nonpsychiatric medications that decrease dopamine activity, such as metoclopramide (Reglan), which blocks D₂ receptors, and tetrabenazine (see Chapter 18), which depletes dopamine from its presynaptic storage vesicles, increase prolactin serum concentration and induce parkinsonism. In contrast, clozapine, which shows little D₂ receptor affinity, does not lead to either of these problems.

Physicians should bear in mind that finding an elevated serum prolactin level does not always indicate use of a dopamine-blocking medication or the presence of a pituitary tumor (see Chapter 19). The most common cause of serum prolactin elevation is pregnancy.

Conditions due to Reduced Dopamine Activity

3. As long as dopamine synthesis continues, neurologists prescribe medicines that slow L-dopa metabolism in the periphery but allow DOPA to continue forming dopamine centrally. Working in that way, two Parkinson disease medications – carbidopa and entacapone – inactivate enzymes that metabolize L-dopa and thereby enhance dopamine activity (see Fig. 18-11). Carbidopa inactivates DOPA decarboxylase. Entacapone inhibits COMT, which normally inactivates L-dopa by converting it to 3-O-methyldopa. Both enzyme inhibitors act almost entirely outside the CNS because they have little ability to penetrate the blood–brain barrier. Therefore, they do not interfere with basal ganglia dopamine synthesis. Giving these enzyme inhibitors along with L-dopa enables small doses of L-dopa to be effective. Moreover, the small doses of dopamine reduce its systemic side effects, such as nausea, vomiting, cardiac arrhythmias, and hypotension.

Commercial preparations combine enzyme inhibitors with L-dopa to prevent its metabolism outside the brain. For example, Sinemet combines carbidopa with L-dopa and Stalevo adds entacapone to carbidopa and L-dopa. As compared to L-dopa alone, L-dopa–carbidopa combinations, such as Sinemet (Latin, sine without, em vomiting), almost completely eliminate the side effects of nausea and vomiting.

Another therapeutic option entails protecting dopamine itself from metabolic enzymes, particularly MAO. Selegiline (deprenyl [Eldepryl]) inhibits MAO-B, one of the two major forms of MAO. Selegiline readily penetrates the blood–brain barrier and, by inhibiting MAO-B, preserves both naturally occurring and L-dopa-derived dopamine. Another advantage of selegiline is that its metabolism yields small amounts of amphetamine and methamphetamine that partially offset Parkinson disease-related fatigue and depression.

Although antidepressant MAO inhibitors inactivate both MAO-A and MAO-B or only MAO-A, selegiline inhibits only MAO-B. In its usual therapeutic dose (≤10 mg) for Parkinson disease treatment, selegiline preserves dopamine but does not place patients, even if they eat tyramine-containing foods, at risk of a hypertensive crisis. Nevertheless, neurologists cautiously use serotonin-enhancing medicines, such as triptans for headaches and selective serotonin reuptake inhibitors for Parkinson disease-induced depression, in patients taking selegiline.

Medication-Induced Parkinsonism.

In contrast to Parkinson disease, where presynaptic neurons have degenerated, medication-induced parkinsonism usually results from blockade of basal ganglia D₂ receptors. This distinction holds great clinical importance when a patient who is under treatment with an antipsychotic agent develops Parkinson disease symptoms. Giving L-dopa at the same time that antipsychotic agents block D₂ receptors may still increase dopamine synthesis, but the dopamine will not affect the receptors or correct the symptoms. More importantly, excess dopamine will stimulate frontal cortex and limbic system dopamine receptors: It may therefore provoke or exacerbate a psychosis. Thus, when a patient who has been treated with an antipsychotic agent – even as recently as 1 month – appears to have developed Parkinson disease, physicians should generally maintain that the patient has iatrogenic parkinsonism; search for alternative diagnoses that can cause both psychosis and parkinsonism, such as dementia with Lewy bodies or Wilson disease; and postpone administering medicines that enhance dopamine.

Neuroleptic-Malignant Syndrome.

An acute absence of dopamine activity causes the parkinson-hyperpyrexia or central dopaminergic syndrome, which neurologists still call the neuroleptic-malignant syndrome (NMS) (see Chapter 6). Administering dopamine agonists may compensate for the absence of dopamine activity and alleviate some of the symptoms, but treatment is generally supportive. Patients usually require parenteral treatment, such an intramuscular injections of the dopamine agonist apomorphine, because the severe muscle rigidity prevents their swallowing pills and the urgency of the situation demands treatment with rapid onset of action.

Conditions due to Excessive Dopamine Activity

Of the several mechanisms that might lead to excessive dopamine activity, the most common is the administration of L-dopa. Cocaine and amphetamine also cause excessive dopamine activity by provoking dopamine release from its presynaptic storage sites and then blocking its reuptake. Some psychiatric medications, such as bupropion (Wellbutrin), also block dopamine reuptake. In a different mechanism, possibly underlying some cases of tardive dyskinesia, increased sensitivity of the postsynaptic receptors results in excessive dopaminergic activity.

Whatever the cause, excessive dopamine activity produces a range of side effects from psychosis to hyperkinetic movement disorders. For example, Parkinson disease patients who take excessive L-dopa may develop visual hallucinations, paranoia, and thought disorders that can reach psychotic proportions. Excessive dopamine activity also produces hyperkinetic movement disorders, such as chorea, tremor, tics, dystonia, and the oral-buccal-lingual variety of tardive dyskinesia.

As a less dramatic example of the effects of excessive dopamine, some Parkinson disease patients become overly involved with stimulating activities, such as sex and gambling. In these cases, neurologists diagnose the dopamine dysregulation syndrome or impulse control disorder (see Chapter 18). They usually ascribe the aberrant behavior to dopamine-induced novelty seeking and inattention.

On the other hand, with a small increase in dopamine activity, as occurs with bupropion treatment, individuals enjoy a sense of well-being. That sensation, however, represents a mere glimmer of a cocaine or amphetamine rush.

In addition to their effects on movements, dopamine and its agonists, acting through the tubero-infundibular tract, inhibit prolactin release from the pituitary gland. Neurologists and endocrinologists prescribe bromocriptine and cabergoline, both dopamine agonists, to shrink pituitary adenomas and suppress their prolactin secretion. In the opposite situation, dopamine receptor blockade of the tubero-infundibular tract by typical neuroleptics and risperidone – but not clozapine or quetiapine – may enhance prolactin release and thereby raise its serum concentration. Patients taking these medicines often report decreased sexual drive and even galactorrhea.

Probably stemming from CNS rather than peripheral nervous system (PNS) dysfunction, habitual cocaine users often experience a paresthesia of ants crawling on or under their skin. Neurologists call this sensation a formication (Latin, formica, ant), but cocaine users call it “coke bugs.”

Norepinephrine and Epinephrine

Synthesis and Metabolism

After the synthesis of dopamine, continuation of the pathway yields norepinephrine and then epinephrine. These neurotransmitters, as well as dopamine, are catecholamines, a subcategory of the monoamines. As with dopamine synthesis, tyrosine hydroxylase remains the rate-limiting enzyme in their synthesis. Also, as with dopamine activity, reuptake and metabolism by COMT and MAO terminate their actions. In contrast to dopamine metabolism, most norepinephrine metabolism takes place outside the CNS. Moreover, its primary metabolic byproduct, which appears in the urine, is vanillylmandelic acid.

Anatomy

CNS norepinephrine synthesis takes place primarily in the locus ceruleus, which is located in the dorsal portion of the pons (Fig. 21-2). Neurons from the locus ceruleus project to the cerebral cortex, limbic system, and reticular activating system. In addition, whereas dopamine tracts remain confined to the brain, norepinephrine tracts project down into the spinal cord.

FIGURE 21-2 Coronal view of the pons, fourth ventricle (IV), and cerebellum. This portion of the brainstem contains paired locus ceruleus (diagonal arrow) and dorsal raphe nucleus (horizontal arrow). The locus ceruleus, which sits lateral and inferior to the fourth ventricle, gives rise to norepinephrine tracts. The dorsal raphe nucleus gives rise to serotonin tracts that spread cephalad, to the diencephalon and cerebrum. A caudal raphe nucleus, in the pons and medulla (not pictured), gives rise to serotonin tracts that spread to the spinal cord.

Also unlike dopamine, norepinephrine serves as the neurotransmitter for the sympathetic nervous system’s postganglionic neurons. In the adrenal gland, a synthetic pathway converts norepinephrine to epinephrine.

Receptors

Norepinephrine receptors are located in the cerebral cortex, brainstem, and spinal cord. The α₂ and β₂ receptors, termed “autoreceptors,” are situated on presynaptic neurons. Through a feedback mechanism, these presynaptic receptors modulate norepinephrine synthesis and release (Fig. 21-3). Postsynaptic receptors are also of two varieties, α₁ and β₁, and they produce varied and sometimes almost opposite effects (Table 21-2).

FIGURE 21-3 In norepinephrine and epinephrine synapses, the postsynaptic neuron has α₁ and β₁ receptors, which initiate the sympathetic “fight or flight” response. The presynaptic neuron has α₂ and β₂ autoreceptors that modulate sympathetic responses (see Table 21-2).

TABLE 21-2 Pharmacology of Epinephrine and Norepinephrine Receptors

^*See Fig. 21-3.

Conditions due to Alterations in Norepinephrine Activity

In Parkinson disease, the locus ceruleus, just like the substantia nigra, degenerates and loses its pigment. Loss of norepinephrine synthesis often leads to orthostatic hypotension, sleep disturbances, and depression.

In the opposite situation, excessive stimulation of β₂-adrenergic sites leads to tremor and bronchodilatation. For example, isoproterenol and epinephrine, particularly when used for asthma, cause tremor as they alleviate bronchospasm. Conversely, β-blockers, which are contraindicated in asthma patients, suppress essential tremor (see Chapter 18).

Although rare, pheochromocytomas are the best-known example of excessive norepinephrine and epinephrine activity. These tumors secrete norepinephrine or epinephrine continually or in erratic bursts. Depending on the pattern, patients have hypertension, tachycardia, and sometimes convulsions.

Serotonin

Synthesis and Metabolism

Serotonin (5-hydroxytryptamine, 5-HT) is another monoamine, but an indolamine rather than a catecholamine. The synthesis of serotonin parallels the synthesis of dopamine – hydroxylation followed by decarboxylation. Although the rate-limiting enzyme in serotonin synthesis is tryptophan hydroxylase rather than tyrosine hydroxylase, hydroxylation remains the rate-limiting step in its synthesis. Also, reuptake and, to a lesser extent, oxidation terminate serotonin activity.

MAO-A metabolizes serotonin to 5-hydroxyindoleacetic acid (5-HIAA). Although platelets, gastrointestinal cells, and other nonneurologic cells synthesize more than 98% of the body’s total serotonin, that serotonin does not penetrate the blood–brain barrier. Thus, CSF concentrations of HIAA reflect CNS serotonin activity. Other enzymes metabolize serotonin to melatonin.

Anatomy

Serotonin-producing CNS neurons reside predominantly in the dorsal raphe nuclei, which are located in the midline of the dorsal midbrain and pons (see Figs 21-2 and 18-2). Serotonin tracts project rostrally (upward) to innervate the cortex, limbic system, striatum, and cerebellum. They also innervate intracranial blood vessels, particularly those around the trigeminal nerve.

Other serotonin-producing nuclei, the caudal raphe nuclei, are located in the midline of the lower pons and medulla. They project caudally (downward) to the dorsal horn of the spinal cord to provide analgesia (see Chapter 14).

Receptors

Studies have identified numerous CNS serotonin receptors (5-HT₁–5-HT₇) and many subtypes. Serotonin receptors differ in their function, response to medications, effect on second-messenger systems, and excitatory or inhibitory capacity. Several serotonin receptors, such as 5-HT_1D, are presynaptic autoreceptors that suppress serotonin synthesis or block its release. In an almost ironic relationship, 5-HT₁ promotes production of adenyl cyclase and is inhibitory, but 5-HT₂ promotes production of phosphatidyl inositol and is excitatory. Other serotonin receptors are usually G-protein-linked and excitatory.

Conditions due to Alterations in Serotonin Activity

Serotonin plays a major role in the daily sleep–wake cycle. The activity of serotonin-producing cells reaches its highest level during arousal, drops to quiescent levels during slow-wave sleep, and disappears during rapid eye movement (REM) sleep (see Chapter 17).

Depression is the disorder most closely associated with low serotonin activity. In the extreme, low postmortem CSF concentrations of HIAA, the serotonin metabolite, characterize suicides by violent means. This finding, one of the most consistent in biologic psychiatry, reflects low CNS serotonin activity. Similarly, individuals with poorly controlled violent tendencies, even those without a history of depression, have low concentrations of CSF HIAA.

Serotonin levels are also decreased in individuals with Parkinson or Alzheimer disease. Among Parkinson disease patients, the decrease is more pronounced in those with comorbid depression.

Sumatriptan and other triptans, a mainstay of migraine therapy, are selective 5-HT_1D receptor agonists. Once stimulated, these serotonin receptors inhibit the release of pain-producing vasoactive and inflammatory substances from trigeminal nerve endings.

A series of powerful antiemetics, including dolasetron (Anzemet) and ondansetron (Zofran), are 5-HT₃ antagonists. By affecting the medulla’s area postrema, one of the few areas of the brain unprotected by the blood–brain barrier, they reduce chemotherapy-induced nausea and vomiting. Similarly, second-generation antipsychotics typically act as antagonists of 5-HT_2A as well as D₂ receptors.

Although increased serotonin activity is often therapeutic, excessive activity poses a danger. For example, combinations of medicines that simultaneously block serotonin reuptake and inhibit its metabolism lead to serotonin accumulation. These combinations may cause toxic levels and the serotonin syndrome (see Chapters 6 and 18).

In another situation characterized by excessive serotonin activity, LSD (D-lysergic acid diethylamide) induces hallucinations and euphoria by stimulating 5-HT₂ receptors. Similarly, “ecstasy” (methylenedioxymethamphetamine [MDMA]), although it also stimulates dopaminergic activity, greatly enhances serotonin activity by triggering a presynaptic outpouring. Ecstasy’s effects surpass LSD’s in stimulating serotonin activity.

Acetylcholine

Synthesis and Metabolism

The combination of acetyl coenzyme A and choline form ACh. Although ACh synthesis depends on the enzyme choline acetyltransferase (ChAT), the rate-limiting factor is the substrate, choline.

Unlike monoamines, ACh does not undergo reuptake. Instead, cholinesterase (the common contraction of acetylcholinesterase) terminates its action in the synaptic cleft. This enzyme hydrolyzes ACh back to acetyl coenzyme A and choline.

Anatomy

In the CNS, most ACh tracts originate in the nucleus basalis of Meynert (also known as the substantia innominata) and adjacent nuclei situated in the basal forebrain (a rostral portion of the brainstem) (Fig. 21-4). These nuclei project their cholinergic tracts throughout the cerebral cortex but particularly to the hippocampus, amygdala, and cortical association areas. In addition, ACh serves as the autonomic nervous system and neuromuscular junction neurotransmitter (see Fig. 6-1).

FIGURE 21-4 This coronal view of the diencephalon, the uppermost brainstem region, shows the nucleus basalis of Meynert, which is situated adjacent to the third ventricle and the hypothalamus.

Receptors

ACh receptors fall into two categories, nicotinic and muscarinic. One or the other predominates in either the cerebral cortex or the neuromuscular junction, produces excitatory or inhibitory actions, and remains vulnerable to different blocking agents (Table 21-3).

TABLE 21-3 Cerebral Cortex and Neuromuscular Junction Acetylcholine (ACh) Receptors

	Cerebral Cortex	Neuromuscular Junction
Predominant ACh receptors	Muscarinic	Nicotinic
Main action	Excitatory or inhibitory	Excitatory
Agents that block receptor	Atropine, scopolamine	Curare, α-bungarotoxin

Conditions due to Reduced ACh Activity at the Neuromuscular Junction

In the PNS, decreased neuromuscular ACh activity – from either impaired presynaptic ACh release or blockade of postsynaptic ACh receptors – leads to muscle paralysis. Conditions that interfere with ACh activity have different etiologies and induce distinct patterns of weakness. For example, in Lambert–Eaton syndrome, the paraneoplastic disorder, antibodies impair the release of ACh from presynaptic neurons and cause weakness of limbs (see Chapters 6 and 19). Botulinum toxin also impairs ACh release from the presynaptic neuron; when ingested as a food poison (botulism), it primarily causes potentially fatal weakness of ocular, facial, limb, and respiratory muscles. When injected into affected muscles for treatment of focal dystonia, medicinal botulinum toxin inhibits forceful muscle contractions because it slows or prevents ACh release from the presynaptic neuron at the neuromuscular junction (see Chapter 18).

At the postsynaptic neuron of the neuromuscular junction, curare, other poisons, and antibodies, such as those associated with myasthenia gravis, each block ACh receptors. The pattern of weakness in myasthenia gravis is distinctive: Patients have asymmetric paresis of the extraocular and facial muscles, but not the pupils. To overcome the ACh receptor blockade in myasthenia gravis, neurologists administer anticholinesterase (the common contraction of antiacetylcholinesterase) medications, such as edrophonium (Tensilon), pyridostigmine, and physostigmine, to inhibit cholinesterase and thereby reduce the breakdown of ACh in the synaptic cleft (see Chapter 6 and Fig. 7-6). The reliability of edrophonium in temporarily reversing myasthenia-induced paralysis has led to the “Tensilon test” (see Fig. 6-4).

Conditions due to Reduced ACh Activity in the CNS

In Alzheimer disease, the cerebral cortex has markedly reduced cerebral ACh concentrations, ChAT activity, and muscarinic receptors (see Chapter 7). In addition, some nicotinic receptors are depleted.

To counteract the ACh deficiency in Alzheimer disease, neurologists have attempted several strategies to enhance its synthesis or slow its metabolism. In hopes of driving ACh synthesis, they have administered precursors, such as choline and lecithin (phosphatidylcholine). Although analogous to providing a dopamine precursor (L-dopa) in Parkinson disease treatment, this strategy failed in reversing the symptoms of Alzheimer disease. A complementary strategy has been to slow ACh metabolism by administering long-acting cholinesterase inhibitors that cross the blood–brain barrier. Several such cholinesterase inhibitors, such as donepezil, may slow the progression of dementia in Alzheimer disease and several other illnesses (see Chapter 7).

Reduced ACh concentrations also characterize trisomy 21, which shares many clinical and physiologic features of Alzheimer disease. Also, the cortex in Parkinson disease and progressive supranuclear palsy (PSP) has reduced ACh concentrations.

Many studies have indicated that an absolute ACh deficiency or, compared to dopamine activity, a relative ACh deficiency causes delirium. Reduced ACh activity leading to cognitive impairment or delirium may occasionally have an iatrogenic basis. For example, scopolamine and other drugs that block muscarinic ACh receptors interfere with memory, learning, attention, and level of consciousness – even when given to normal individuals. In fact, scopolamine, which readily crosses the blood–brain barrier, induces a transient amnesia that has been a laboratory model for Alzheimer disease dementia.

Anticholinergic Syndrome

Chlorpromazine, other typical antipsychotic agents, and tricyclic antidepressants may block muscarinic ACh receptors and cause physical anticholinergic side effects, including drowsiness, dry mouth, urinary hesitancy, constipation, and accommodation paresis (see Chapter 12). Anticholinergic activity may also rise in individuals taking nonpsychiatric medicines, such as atropine, scopolamine, benztropine, and trihexyphenidyl. With enough anticholinergic activity, individuals develop the anticholinergic syndrome: dilated pupils, elevated pulse and blood pressure, dry skin and hyperthermia, and delirium that may progress to coma. In this situation physicians may administer physostigmine, an anticholinesterase that crosses the blood–brain barrier, to restore ACh activity.

Conditions due to Excessive ACh Activity

ACh intoxication takes the form of a massive, predominantly muscarinic parasympathetic discharge. Its primary features consist of bradycardia, hypotension, miosis, and a characteristic outpouring of bodily fluids in the form of excess lacrimation, salivation, bronchial secretions, and diarrhea. Depending on the poison, dose, and route of entry, victims may show signs of CNS involvement, which may include delirium, slurred speech, and seizures. Sometimes they may also show signs of PNS involvement, such as generalized flaccid paresis and fasciculations.

Medications, homicide, suicide, or accidents at home or work may lead to ACh poisoning. In most cases, inactivation of cholinesterase leads to a toxic accumulation of unmetabolized ACh in the brain, autonomic ganglia, and neuromuscular junction. For example, patients with dementia who accidentally take too many donepezil pills or apply rivastigmine patches without removing the old ones may eliminate their cholinesterase and allow an excess of unmetabolized ACh to accumulate. Similarly, eating certain mushrooms will also cause ACh toxicity. Individuals may suffer from exposure to common organophosphorus insecticides, such as parathion and Malathion, or they may swallow a Latin American rat poison, tres pasitos, which looks like grains of rice. Ingestion of these poisons may be the result of suicide or homicide attempts as well as occupational exposure. Similarly, many poison gases, such as the terrorist gas sarin, raise ACh concentrations to toxic levels.

Supporting vital functions, especially respiration, is essential. The specific treatment of ACh poisoning from organophosphate ingestion, which is probably the most common scenario, consists of the administration of atropine, which is a competitive inhibitor of ACh at muscarinic receptors, to reverse the parasympathetic overactivity, and pralidoxime to reactivate cholinesterase activity. Health care workers should remain aware that the poison often saturates the clothing of victims.

Neuropeptides

Gamma-Aminobutyric Acid – An Inhibitory Amino Acid Neurotransmitter

Synthesis and Metabolism

GABA and, to a lesser extent, glycine are the brain’s major inhibitory neurotransmitters. Glutamate, decarboxylated by the enzyme glutamate decarboxylase (GAD), forms GABA. An important aspect of the synthesis is that GAD requires vitamin B₆ (pyridoxine) as a cofactor. GABA undergoes reuptake or metabolism by several enzymes.

Anatomy

Reflecting its widespread and critical role in inhibition, GABA is distributed throughout the entire CNS. However, it is concentrated in the striatum, hypothalamus, spinal cord, and temporal lobe.

Receptors

The two GABA receptors, GABA_A and GABA_B, are complex molecules. GABA_A receptors, which are more numerous and important than GABA_B receptors, are gated to various molecules called ligands. The receptors have binding sites for benzodiazepines, barbiturates, alcohol, and some antiepileptic drugs (AEDs).

When activated by these ligands, GABA_A receptors open chloride channels, and this allows negatively charged chloride ions (Cl^–) to flow into the cell. The influx of these negatively charged ions into neurons lowers (makes more negative) their resting potential, which is normally –70 mV. GABA-induced lowering of the resting potential, which hyperpolarizes the membrane, has an inhibitory effect on the cell. Because of the rapidity of this hyperpolarization, which is based on changes in the permeability of ion channels, neuroscientists consider GABA and several other neurotransmitters as “fast.”

The GABA_B receptor, a G protein coupled to calcium and potassium channels, is also inhibitory. Baclofen, which counteracts spasticity, dystonia, and neuropathic pain, binds to this receptor. In contrast to the large numbers of ligands that bind to the GABA_A receptor, baclofen is one of the few that binds to the GABA_B receptor. Other medicines that alleviate spasticity act through different mechanisms. For example, tizanidine (Zanaflex) acts as an α₂-adrenergic agonist and dantrolene (Dantrium) reduces muscle contraction by acting directly on muscles.

Conditions due to Alterations in GABA Activity

GABA deficiency is characterized by a lack of inhibition, which leads to excessive activity. For example, in Huntington disease, depleted GABA reduces inhibition in the basal ganglia, presumably leading to excessive involuntary movement, typically chorea. Tetanus and strychnine poisoning each illustrate the effects of decreased GABA activity (see later).

In the stiff-person syndrome, formerly known as the stiff-man syndrome, anti-GAD antibodies reduce GABA synthesis. The reduced GABA activity in this disorder leads to muscle stiffness and gait impairment that physicians might mistake for catatonia or an acute dystonic reaction to antipsychotic agents; however, the symptoms are not so acute or severe that neurologists might diagnose tetanus or strychnine poisoning. Neurologists usually diagnose the stiff-person syndrome by finding anti-GAD antibodies in the serum and CSF. In many cases, the stiff-person syndrome is associated with an underlying neoplasm, such as breast cancer, or various autoimmune diseases. Whatever the cause, immunomodulation and diazepam usually alleviate the stiffness.

Diets deficient in pyridoxine, the cofactor for GAD, impair GABA synthesis and cause seizures. Likewise, overdose of isoniazid (INH), which interferes with pyridoxine, occasionally leads to seizures. In both cases, the seizures respond to intravenous pyridoxine.

Several AEDs are effective, in part, because they increase GABA activity. For example, valproate (Depakote) increases brain GABA concentration. Tiagabine (Gabitril) inhibits GABA reuptake. Topiramate (Topamax) enhances GABA_A receptor activity. Vigabatrin (Sabril) increases GABA concentrations by reducing its metabolic enzyme, GABA-transaminase.

In a different situation, flumazenil, a benzodiazepine antagonist, blocks the actions of GABA at its receptor and reverses benzodiazepine-induced stupor and hepatic encephalopathy. In the case of hepatic encephalopathy, flumazenil presumably displaces false, benzodiazepine-like neurotransmitters from GABA receptors (see Chapter 7).

Glycine – Another Inhibitory Amino Acid Neurotransmitter

Synthesis, Metabolism, and Anatomy

Glycine, while a simple amino acid and not essential to the human diet, acts not only as a powerful inhibitory neurotransmitter but also paradoxically as a co-agonist or modulator of the excitatory neurotransmitter glutamate at NMDA receptors. The enzyme hydroxymethyl transferase converts the amino acid serine to glycine. Several different metabolic pathways inactivate it.

Glycine’s inhibitory activity affects the ventral horn of the spinal cord, which is the site of motor neurons, and the brainstem. Under normal circumstances, glycine provides inhibition of muscle tone that balances the excitation of muscle tone provided by other neurotransmitters.

Conditions due to Alterations in Glycine Activity

Reduced glycine activity characterizes tetanus and strychnine poisoning. In both conditions, loss of inhibitory activity causes patients to suffer from unrelenting powerful muscle contractions. In tetanus (see Chapter 6), the toxin (tetanospasmin) prevents the presynaptic release of glycine and GABA. Due mostly to the loss of glycine-induced muscle inhibition, tetanus patients suffer “tetanic contractions” of limb, facial, and jaw muscles, typically manifest as “lockjaw.” In a different mechanism of action but with similar results, strychnine blocks the postsynaptic glycine receptor. Strychnine poisoning leads to fatal limb, larynx, and trunk muscle contractions.

Glutamate – An Excitatory Amino Acid Neurotransmitter

Synthesis, Metabolism, and Anatomy

Glutamate, a simple amino acid synthesized from glutamine, is the most important excitatory neurotransmitter. Reuptake into presynaptic neurons and adjacent support cells terminates glutamate activity. To a lesser extent, glutamate undergoes nonspecific metabolism. Its tracts project throughout the brain and spinal cord.

Aspartate is another excitatory amino acid. However, compared to glutamate, its anatomy and clinical importance are less well established.

Receptors

Of several glutamate receptors, N-methyl-D-aspartate (NMDA) is the most important. It has binding sites for glycine, phencyclidine (PCP), and a PCP congener, ketamine (see later). Through its interactions with NMDA receptors, which regulate calcium channels, glutamate acts as a fast neurotransmitter.

Conditions due to Alterations in NMDA Activity

Excessive NMDA activity floods the neuron with potentially lethal concentrations of calcium and sodium in several disorders. Through this process, excitotoxicity, glutamate–NMDA interactions lead to neuron death through apoptosis. Excitotoxicity may be intimately involved in the pathophysiology of epilepsy, stroke, neurodegenerative diseases (such as Parkinson and Huntington diseases), head trauma, and, conceivably, schizophrenia. In certain paraneoplastic syndromes, particularly one triggered by ovarian teratomas in young women, antibodies directed toward NMDA receptors create an autoimmune limbic encephalitis (see Chapter 19).

Consequently, one approach to stemming the progression of neurodegenerative diseases has been to use medicines that block glutamate–NMDA interactions. Despite this rationale, such medicines provide only a modicum of neuroprotection. For example, riluzole (Rilutek), which decreases glutamate activity, only transiently interrupts the progression of amyotrophic lateral sclerosis. Similarly, memantine (Namenda), an NMDA receptor antagonist, blocks its deleterious excitatory neurotransmission and slows the progression of Alzheimer disease for approximately only 6 months. Also, the AEDs, gabapentin and lamotrigine, are glutamate antagonists.

Despite the benefit of blocking glutamate in various diseases, deficient NMDA activity can also be harmful. For example, PCP and ketamine may block the NMDA calcium channel and cause psychosis.

Other Neuropeptides

Endorphins, enkephalins, and substance P, which are situated in the spinal cord and brain, provide endogenous analgesia in response to painful stimuli (see Chapter 14). Substance P and, to a lesser degree, other neuropeptides are depleted in Alzheimer disease. The other neuropeptides that are reduced include somatostatin, cholecystokinin, and vasoactive intestinal peptide.

A pair of neuropeptides, hypocretin-1 and -2, also known as orexin A and B, are excitatory neurotransmitters that play a crucial – but an ill-defined – role in locomotion, metabolism, appetite, and the sleep–wake cycle (see Chapter 17). Synthesized in the hypothalamus, where they are cleaved from a large precursor protein, these neuropeptides increase during wakefulness and REM sleep, and decrease during non-REM sleep. Unlike normal individuals, narcolepsy patients have little or no hypocretin in their CSF and their hypothalamus is devoid of hypocretin-producing cells.

Nitric Oxide

Synthesis and Metabolism

Nitric oxide (NO), the product of a complex synthesis, is an important neurotransmitter for endothelial cells and the immunologic system. NO should not be confused with nitrous oxide (N₂O), which is a gaseous anesthetic (“laughing gas”). N₂O, when inhaled daily as a form of drug abuse, leads to vitamin B₁₂ deficiency, which results in cognitive impairment and spinal cord damage (combined system disease).

Important in many roles, NO inhibits platelet aggregation, dilates blood vessels, and boosts host defenses against infections and tumors. From a neurologic viewpoint, its main functions include regulating cerebral blood flow and facilitating penile erections. It may also have a CNS neuroprotective effect.

Receptors

NO diffuses into cells and interacts directly with enzymes and iron–sulfur complexes; however, it has no specific membrane receptors.

Conditions due to Alterations in NO Activity

The best-known role of NO is in generating erections (see Chapter 16). With sexual stimulation of the penis, parasympathetic neurons produce and release NO. NO then promotes the production of cyclic guanylate cyclase monophosphate (cGMP), which dilates the vascular system and creates an erection. Sildenafil slows the metabolism of cGMP and increases blood flow in the penis, which, in turn, produces, strengthens, and prolongs erections.